Stanley Miller's most famous scientific work was conducted in 1953, while he was a young graduate student at the University of Chicago. Working under Nobel laureate Harold C. Urey, he placed small amounts of methane, ammonia, hydrogen and water -- but no oxygen -- in an airtight container, then heated it and subjected it to electrical sparks -- an attempt to approximate early earth atmosphere and weather. Although his work had been inspired by Urey's theories, Urey initially discouraged Miller from attempting the experiment, thinking it would take years, long after Miller's graduate studies ended, before it could yield any conclusive results.

But in a matter of mere weeks, chemical reactions had produced thirteen of the amino acids necessary for life, showing that these building blocks of proteins could be spawned from the simplest chemicals. Commonly called the Miller-Urey experiment, this is considered the seminal experiment on the origin of life. Carl Sagan described it as "the single most significant step in convincing many scientists that life is likely to be abundant in the cosmos." When Miller prepared his report for the journal Science, he credited Urey as co-author, as is traditional, but Urey crossed his name off the paper. "I already have a Nobel Prize," he reportedly said. Sadly, Miller never received one of his own, and no-one has yet followed Miller's work by showing how these chemicals are assembled into living cells.

In addition to its scientific impact, as Miller's work was reported in the media it also popularized the public conception of "primordial ooze" or "prebiotic soup".